High Plant Protein Diet Ameliorated Hepatic Lipid Accumulation Through the Modulation of Gut Microbiota

Scope Substituting plant protein for animal protein has emerged as a promising strategy for managing atherogenic lipids. However, the impact of long‐term intake of a high plant protein diet (HPD) on hepatic lipid disorder remains unclear. Methods and results Eight‐week‐old apolipoprotein E deficient (apoE−/−) mice are fed with either a normal protein diet (NCD) or HPD for 12 weeks. HPD intervention results in decreased body weight accompanied by increased energy expenditure, with no significant effect on glycemic control. Long‐term intake of HPD improves the serum and hepatic lipid and cholesterol accumulation by suppressing hepatic squalene epoxidase (SQLE) expression, a key enzyme in cholesterol biosynthesis. Integrated analysis of 16S rDNA sequencing and metabolomics profiling reveals that HPD intervention increases the abundance of the Lachnospiraece family and serum levels of 12,13‐DiHOME. Furthermore, in vivo studies demonstrate that 12,13‐DiHOME significantly inhibits lipid accumulation, as well as SQLE expression induced by oleic acid in HepG2 cells. Conclusion Diet rich in plant protein diet alleviates hyperlipidemia via increased microbial production of 12,13‐DiHOME. Schematic summary illustrating the potential mechanism whereby high plant protein diet ameliorates hepatic cholesterol accumulation in apoE−/− mice. Long‐term intake of HPD reshapes the gut microbiota and increases the production of 12,13‐DiHOME, which in turn prevents hepatic lipid accumulation via suppressing the expression of SQLE.